The treatment of chronic and non-chronic pain is of great importance in medicine. There is a worldwide need for highly effective therapies for pain. The urgent need for action for a treatment for pain that is fair to the patient and targeted, which is to be understood as meaning the successful and satisfactory treatment of pain for the patient, is documented in the large number of scientific works that have recently appeared in the field of applied analgesia or fundamental research into nociception.
Conventional μ-opioids such as morphine are highly effective in the therapy of strong to very strong pain and are of great importance in the therapy of pain. However, it can be advantageous to influence other opioid receptors, in particular the ORL-1 receptor, in addition to the μ-opioid receptor, because the pure μ-opioids also exhibit undesirable side-effects, such as constipation and respiratory depression, and can also lead to dependency. The opioid receptors δ, κ and ORL-1 are also involved in the occurrence of pain (Opioids: Introduction, p. 127-150, Further Opioid Receptors, 455-476 in: Analgesics—From Chemistry and Pharmacology to Clinical Application, Wiley VCH, 2002).
It is also known that influencing serotonin and/or noradrenaline reuptake can have an advantageous effect on the spectrum of action and side-effects of opioids (example: tramadol, see Opioids with Clinical Relevance: Tramadol, 228-230 in: Analgesics—From Chemistry and Pharmacology to Clinical Application, Wiley VCH 2002).
The ORL1 receptor is additionally also involved in the regulation of further physiological and pathophysiological processes. These include inter alia learning and memory formation (Manabe et al., Nature, 394, 1997, p. 577-581), hearing ability (Nishi et al., EMBO J., 16, 1997, p. 1858-1864) and numerous further processes. In an overview article by Calo et al. (Br. J. Pharmacol., 129, 2000, 1261-1283), an overview is given of the indications or biological processes in which the ORL1 receptor plays or with high probability might play a role. Those mentioned are, inter alia: analgesia, stimulation and regulation of food intake, influence on μ-agonists such as morphine, treatment of withdrawal symptoms, reduction of the addictive potential of opioids, anxiolysis, modulation of motor activity, memory disorders, epilepsy; modulation of neurotransmitter secretion, in particular of glutamate, serotonin and dopamine, and therefore neurodegenerative diseases; influencing of the cardiovascular system, initiation of an erection, diuresis, antinatriuresis, electrolyte balance, arterial blood pressure, water retention diseases, intestinal motility (diarrhoea), relaxing effects on the respiratory tract, micturition reflex (urinary incontinence). The use of agonists and antagonists as anoretics, analgesics (also in co-administration with opioids) or nootropics is furthermore discussed.
From the prior art (WO 02090317) there are known structurally related compounds that have an affinity for the ORL-1 receptor. No influence on noradrenaline and serotonin reuptake has hitherto been described for this structural class.